This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIMS: The psychostimulants modafinil and its active isomer armodafinil are currently approved in the US for the treatment of narcolepsy. The rapidly expanding therapeutic indications for modafinil, combined with its "atypical" designation, create an exigency to clarify modafinil effects on dopaminergic systems in living brain. As armodafinil is more potent, has a longer duration of action, and contains no inactive component, compared with racemic modafinil, we postulated that armodafinil will occupy a significant proportion of DAT sites in brain and that occupancy would be associated with increased extracellular dopamine concentrations. METHODS: DAT was monitored with (11C)altropane and extracellular dopamine levels were measured indirectly by .D2 dopamine receptor occupancy with (11C)raclopride. RESULTS: Armodafinil occupied the DAT dose-dependently, with high occupancies (61 - 65 percent0 at the 250 mg dose. PET results revealed modest increases in extracellular dopamine levels, at both doses. CONCLUSIONS: Clarifying whether this class of anti-narcoleptics exert their therapeutic benefits through enhancement of dopamine signaling has important clinical and scientific implications. As armodafinil occupies the DAT and raises extracellular dopamine levels, it validates our previous findings with racemic modafinil in nonhuman primates and supports its use in dopamine-related disorders, such as ADHD. It furthermore raises interest in the therapeutic potential of low affinity DAT inhibitors, as well as the potential abuse liability of this previously designated "atypical" drug.